SE454173B - 4H-1,2,4-TRIAZOLD DERIVATIVES FOR USE AS THERAPEUTIC, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE DERIVATIVES, NEW 4H-1,2,4-TRIAZOLD DERIVATIVES AND PROCEDURE FOR THEIR PREPARATION - Google Patents

Description

H1 (Ing) h) ab wherein R1, R2, R3 and R, the same or different, at any position in the benzene nucleus, represent a hydrogen atom, a hydroxyl group, an alkyl group having 1-4 carbon atoms, an Oalk1, wherein alk1 represents an alkyl group having 1-4 carbon atoms, a group NH2, NHalk2, wherein alkz represents an alkyl group having 1-4 carbon atoms, a group alk'3 N-alk 3 alkyl group having 1-4 carbon atoms, a halogen atom, a group CF3 or NO 2, or R 1 and R 2 and / or R 3 and R 4 together form a methylenedioxy group, R "represents an ethyl, n-propyl, n-butyl group, wherein alk 3 and alk '3, the same or different, represent a group -CH 2 CO 2 H, or -CH 2 CO 2 alks, wherein alk 5 represents an alkyl group having 1-4 carbon atoms, and addition salts thereof with acids.

Among the addition salts with acids are those formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric or phosphoric acid or organic acids such as acetic acid, propionic acid, maleic acid or hemisuccinic acid.

When R, R 1, R 2, R 3 and R 4 represent an alkyl group PPP, it is preferably the methyl, ethyl, n-propyl, isopropyl or n-butyl group.

Alk 1 is a methyl, ethyl, n-propyl, isopropyl or n-butyl group. , alkz, alk3, alk'3, alk4 and alks preferably denote When R1, R2, R3 and R4 denote a halogen atom, it is preferably a fluorine, chlorine, bromine or iodine atom, and preferably chlorine or bromine.

Among the compounds of formula (I), mention is made in particular of those compounds of formula (I ')' R 45 R 17 R 1 Ru wherein R 1, R 2, R 3 and R 4 have the meanings given above, R 'represents a group a1k4, alk4 represents an alkyl group having 1-4 carbon atoms, a group -CH2 CO2H, or -CH2 CO2 an alkyl group having 1-4 carbon atoms, and addition salts thereof with alks, wherein alks represent acids.

Among the compounds of formula (I '), mention is made in particular of those compounds which have the formula (I ") N - N» in NR' R'1 (I ") RIB RI" wherein R'1, R'2, R '3 and R' 4, the same or different, in any position on the benzene nuclei, denote the above values for R 1 may simultaneously denote a hydrogen atom, R 'has the meanings given above, R 2, R 3 and R 4, wherein R 1, R 2, R 3 and R 4, however, do not see as well as addition salts thereof with acids.

The invention relates in particular to those compounds of formula (I), (I ') or (I ") for which R or R' represents an alkyl group having 2 to 4 carbon atoms, a group -CH 2 CO 2 H or -CH 2 CO 2 alks, wherein alks contain 1-4 carbon atoms, as well as addition salts thereof with acids.

The invention relates in particular to those compounds of formula (I), (I ') or (I ") for which R or R' represents an alkyl group and their addition salts with acids, for use as a therapeutic.

Among the preferred compounds of the invention there may be further mentioned those compounds of formula (I), (I ') or (I ") for which R or R' represents a hydrogen atom, and their addition salts with acids, those for which R 2 or R '2 represents a group Oalk 1, in any position in the benzene nucleus and in particular a methoxy group in the 4-position, and addition salts thereof with acids, Mention may also be made of the compounds for which R 3 or R' 3 represents a hydrogen atom and R 4 or R '4 a methoxy group, a chlorine atom, a group CF 3, a methyl group or a NO 2 group, in any position on the benzene nucleus, and their addition salts with acids, and in particular the compounds for which R 3 or R'3 represents a methoxy group in the 4-position, and R4 or R'4 have the meanings given above, as well as addition salts thereof with acids.

The invention relates in particular to those compounds, the preparation of which is given below in the experimental part.

Preferred compounds of the invention are the products prepared in Examples 1, 25 and 28.

The compounds of formula (I) and salts thereof have interesting pharmacological properties and they have in particular a remarkable analgesic effect.

These properties make the products of formula (I) and their addition salts with pharmaceutically acceptable acids useful in therapy.

The invention thus relates in particular as medicaments to the compounds of formula (I), as defined above, and to their addition salts with pharmaceutically acceptable acids.

The invention relates in particular as medicaments to the products of Examples 1, 25 and 28 and their addition salts with pharmaceutically acceptable acids.

N-454 173 The medicaments according to the invention can be used in the treatment of muscle allergies, articular or nervous, tooth pain, migraines, as well as in the treatment of rheumatic disorders.

The invention relates to the pharmaceutical compositions which contain as active ingredient the medicaments defined above.

These pharmaceutical compositions may be administered orally, rectally or parenterally or topically by topical application to the skin and mucous membranes.

These compounds are solids or liquids and are present in the pharmaceutical forms commonly used in human medicine, such as e.g. single or coated tablets, gelatin capsules, granules, suppositories, injectable preparations, pomades, creams, gels and aerosol preparations. They are produced by the usual methods. The main active ingredient may be incorporated therein with excipients commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, vehicles, aqueous or not, fats of animal or vegetable origin, paraffinic derivatives , glycols, various wetting, dispersing or emulsifying agents, preservatives.

The daily dose varies in particular depending on the mode of administration, the treated condition and the individual concerned.

In the adult, it can e.g. vary between 50 mg and 2 g of main active ingredient per day when administered orally.

The invention also relates to a preparation process for the compounds of formula (I "'), and their salts, characterized in that a compound of formula (II) H1? - rim ñ WR" (II) H1 oo uw' 454 173 is exposed in which E1, R2 and ï have the meanings given above, for the action of a compound of the formula (III) / NHz 3 (III) Ru n wherein R3 and Ru have the meanings given above, in the presence of a dehydrating agent for the preparation of the corresponding the compound of the formula (I "') fi'" _ 'NI Rl e N ÅR "if) H2 R3 Ru which, if desired, is subjected to the action of an acid to produce the salt therefrom.

According to a preferred embodiment, the dehydrating agent is phosphorus trichloride or phosphorus anhydride.

The products of formula (II) used as starting materials are generally known products which can be prepared by the process described by HORWITZ ET COLL J.

Org, šg 19A-201 (195ü) by reacting an acid of the formula _ OZH R or a functional derivative 1 Ra 454 175 of this acid, with a compound of the formula RCONHNH2, wherein R1, R2 and R have the meanings given above.

Some products of formula (II) are new such as e.g. 2- (1-oxopropyl) -hydrazide of 4-methoxybenzoic acid, 2- (1-oxo-butyl) -hydrazide of H-methoxybenzoic acid, 2- (1-oxopentyl) -hydrazide of N-methoxybenzoic acid, 2- (1-oxo -2-methyl-propyl) -hydrazide of H-methoxy-benzoic acid, 2- (1-oxopropyl) -hydrazide of U-chlorobenzoic acid, 2- (1-oxopropyl) -hydrazide of 3,1-methylene-dioxibenzoic acid, and 2 - (1-oxopropyl) -hydrazide of 3,4-dimethoxyenoic acid, and the invention thus relates to these products as new industrial compounds, and in particular as necessary intermediates for carrying out the process according to the invention.

The invention relates to a variant of the process described above, characterized in that a compound of the formula (IV) C 1 NH (iv) in which R 1, R 2, R 3 and Ru are defined as before, is subjected to the action of hydrazine for the preparation of a compound of the formula (V) 454 173 N - NH 1 I (v) S OIIl man - either exposed to the action of an acid or a functional derivative of an acid XCO 2 H, wherein X represents a hydrogen atom or an alkyl group having 1 - H carbon atoms , for the preparation of a compound of formula (VI): (VI) Ru which is cyclized by heating to prepare the compound of formula (IA) N '- N 454 173 corresponding to a compound of formula I "', wherein R 1, R 2, R B and Ru are as defined above, and X represents an ethyl, n-propyl, n-butyl group, as previously defined, which compound of formula (IA) is, if desired, subjected to the action of a acid to produce the salt therefrom, - or subject to the action of a compound of formula (VII): Hal - C - CH 2 - CO 2 - a lks (VII) wherein Hal represents a halogen atom and alk5 is defined as before, for the preparation of the compound of formula (IB): corresponding to a compound of formula I ", vani R1, H2, R3 and Ru are defined as before, and R "represents a group -CH 2 CO 2 -alk 5, wherein alks is defined as before, which compound of formula (IB) is, if desired, subjected to the action of an acid to produce therefrom the salt, or which compound, if if desired, subject to the action of an acid hydrolyzing agent to prepare the compound of formula (IC): 454 173 (I corresponding to a compound of formula I, wherein B1, R2, R3 and Ru are defined as above, and R denotes a group -CH 2 -CO 2 H, which compound of formula (IC) is, if desired, subjected to the action of an acid- to produce the salt therefrom.

According to a preferred embodiment of the invention - the functional acid derivative XCOEH used is an anhydride, an ester or an acid halide, e.g. an acid chloride, - Hal denotes a chlorine atom, - the hydrolysing agent is hydrochloric acid.

It is obvious that one can perform for a chemist obvious variations of the substituents R1, R2, R5 and Ru, when a compound of formula I is prepared once. One can e.g. esterify or esterify a hydroxyl, cleave a group O 0 alkyl or 0 acyl to obtain a hydroxyl group, transfer the group NO 2 to a group NH 2 or to a group N (alkyl) 2. Examples of such modifications are given below in the experimental section.

The intermediate products obtained during the execution of the procedure are new products. The compounds of formula (IV) H1 (IV) are compounds which can be prepared by the procedure set forth in Ann. Chem. 716 209-211 (1968), for the preparation of U-methoxy-H'-nitrothiabenzanilide by reacting a compound of the formula wherein H1 and R2 have the meanings given above, and Hal represents a halogen atom, having a compound of the formula HZN Ru in which R5 and Ru have the meanings given above, for the preparation of the compound of formula 454 173 Ru n. Which is subjected to the action of phosphorus pentasulfide P2S5 in the presence of a tertiary amine e.g. pyridine for the preparation of the corresponding compound of formula (IV).

Among the compounds of the formula (IV), a new one, namely U-dimethylamino-U'-methoxy-thiobenzanilide, and as a new chemical product, in particular as a necessary intermediate for carrying out the process according to the invention, is one of the objects of the invention.

The following examples describe the invention without limiting it in any way.

Example 1: 3,1-bis- (U-methoxyphenyl) -5-ethyl-αH-1,2,1-triazole.

Under an inert atmosphere, a solution of 0.1 ml of phosphorus trichloride in 50 ml of o-dichlorobenzene is added dropwise over 50 minutes to a solution containing 33.2 g of anisidine in 100 ml of o-dichlorobenzene. Heat at 90 DEG-1000 DEG C., maintain this temperature for 15 minutes and add 10 g of 2- (1-oxopropyl) -hydrazide of U-methoxybenzoic acid. The reaction mixture is heated at 2000 DEG C. and the dichlorobenzene is refluxed for 3 hours. Allow to cool, pour on ice, acidify with 50 ml of 2N hydrochloric acid, add water and ether. Stir, decant, wash with ether, treat the resulting aqueous solution with activated carbon and filter.

A concentrated sodium hydroxide solution is added dropwise. The resulting precipitate is filtered and dried. Thus, 10.75 g of the desired product with a melting point of 120 DEG-125 DEG C. are obtained.

Eral fl sßëll fl i fl ss_2; <9.Pz ° 2vl>; hz <1: aai9 avJtmatexi- §ens9e§yra¿ 20 g of the H-methoxybenzoic acid hydrazide (prepared by the procedure described in Beílstein lg I 78) and 75 ml of propionic anhydride are mixed . The mixture is heated at 700 DEG C. and kept at this temperature for 15 minutes. The excess anhydride is removed, the residue is taken up in petroleum ether (boiling point 60 DEG-800 DEG C.), ice-cooled and filtered. There is thus obtained 25 .mu.g of the desired product with a melting point of 1350 DEG C. Example 2: The hydrochloride of 3,1H-bis (α-methoxyphenyl) -5-ethyl-HH-1,2, N-triazole.

Dissolve 5 of the product prepared in Example 1 in 5 ml of ethanol in the presence of 2.9 ml of a hydrochloric acid solution in ethanol 5.9N. Stir and add isopropyl ether. Stir while stirring for 2 hours, filter, stir to a dough with isopropyl ether and dry under reduced pressure. Thus, H, 4 g of the desired product are recovered.

Example 3: 3-Ethyl-5- (4-methoxyphenyl) -U- (2-methylphenyl) -H-1,2-triazole.

The procedure is as in Example 1, starting from U, H ml of phosphorus trichloride, 150 ml of o-dichlorobenzene, 28.8 ml of o-toluidine and g of 2- (1-oxopropyl) -hydrazide of U-methoxybenzoic acid. 7.4 g of the desired product with a melting point of 118 DEG C. are obtained.

Example U: 3-Ethyl-5- (U-methoxyphenyl) -N- [3- (trifluoromethyl) -phenyl] -HH-1,2,2-H-triazole. 454. 173 l1 The procedure is as in Example 1 starting from U3, 11 g of m-trifluoromethylaniline, 150 ml of o-dichlorobenzene, U, U ml of phosphorus trichloride and 10 g of 2- (1-oxopropyl) -hydrazide of H-methoxybenzoic acid. 6.65 g of the desired product with a melting point of 10 ° C.

Example 5: H- (U-chlorophenyl) -3-ethyl-5- (H-methoxyphenyl) -HH-1,2,4-triazole.

The procedure is as in Example 1, starting from 3U, 1H g of p-chloroaniline, 150 ml of o-dichlorobenzene, U, U ml of phosphorus trichloride and 10 g of 2- (1-oxopropyl) -hydrazide of U-methoxybenzoic acid. 8.2 g of the desired product, m.p. 175 DEG-176 DEG C. Example 6: 5-Ethyl-5- (H-methoxyphenyl) -4-phenyl-HH-1,2,4-triazole.

G of 2- (1-oxopropyl) -hydrazide of U-methoxybenzoic acid, 22.5 g of phosphoric anhydride and 200 ml of aniline are heated under an inert atmosphere for 2 hours at 160 DEG C. As much aniline as possible is distilled under reduced pressure. The residue is resumed in a mixture of ether and ammonia-containing water. The aqueous phase is separated, the ether phase is washed with water. You dry and bring to dryness. It is recrystallized by heating in a mixture of 600 ml of cyclohexane and 150 ml of benzene. Treat with activated carbon, filter, evaporate to about 250 ml. It is then allowed to crystallize and thus 10 g of the desired product with a melting point of 18 ° C are recovered.

Example 7: Hydrochloride of 3-ethyl-5- (N-methoxyphenyl) -U-phenyl-UH-1,2,3-triazole.

5.1 g of the product prepared in Example 6 are dissolved in 5.1 ml of ethanol. 2.85 ml of a hydrochloric acid solution in ethanol 6, HN, then isopropyl ether are added. Filter, stir to a dough several times with isopropyl ether and dry. The product obtained is recrystallized by dissolving it in 350 ml of tetrahydrofuran. Filter to remove insoluble matter and then evaporate the tetrahydrofuran to 75 ml. Allow to cool and cool.

Filter, wash with tetrahydrofuran and dry.

3.3 g of the desired product are recovered, which melts with decomposition at 15 ° C.

Example 8: 3- (U-methoxyphenyl) -α-phenyl-5-methyl-UH-1,2,1-triazole.

By working as in Example 1 starting from 26.5 ml of aniline, 150 ml of α-dichlorobenzene, H, 65 ml of phosphorus chloride and 10 g of N - (U-methoxybenzoyl) -N '- (acetyl) -hydrazine, prepared the procedure described in J. Org. 19 N-201 (l95ü) 7.1 g of the desired product are obtained with a melting point of 140-111 ° C.

Example 9: 3- (N-methoxyphenyl) -4-phenyl-HH-1,2,1-triazole.

By working as in Example 1 starting from 28.2 ml of aniline, 150 ml of 0-dichlorobenzene, M, 95 ml of phosphorus trichloria and 10 g of N-anisoyl-N'-formylhydrazine, prepared by the procedure described in Ann. elk 250 (93U), 7 g of the desired product with a melting point of 139 DEG-140 DEG C. are obtained.

Example 10: 3-Ethyl-5- (U-methoxyphenyl) -H- (β-nitrophenyl) -HH-1,2,2-triazole. êtsaü l-mevzsirll; <1-91212fsnzll-äeaßsfckarwavársZenemidl Reflux a mixture containing 10 g of ü-methoxy-''-nitrothiobenzanilide, prepared by the method of Ann. Chem. 11 209-211 (1968), 100 ml of ethanol and 15 ml of hydrazine hydrate. Allow to return to room temperature. It is centrifuged, washed with ethanol and dried at 800 DEG C. under reduced pressure. 7.9 g of the desired product are obtained, which melts at 10 DEG-4 DEG C. 'ê fi ssåi ï-.faei ° æi; N; (ï-aiirefe fl ill-ä';. Z äeaSefukefäwvâraze fl ef fl idi. in a suspension containing 1.0 g of the product prepared in step A, 1 ml of anhydrous benzene and 0.1 ml of pyridine, stirring for 30 minutes, centrifuging, washing with benzene to give 1.45 g g of the desired product, melting at 20 ° C. â fi esßi â-e fi zl fi; <ï¶eä ° æißayl> ät <ï-aiärefs fl ill-i fi; lßê fl äfåfiašoš 'Heat at 250 - 3000 C 1.2 g of the product, prepared in step B, allowed to cool once the evolution of gas has been completed, washed with ethanol, centrifuged and dried to give the desired product, giving 0.9 g of the desired product, melting at 178 DEG C.

Example 11: §, U-bis- (N-methoxyphenyl) -Spropyl-HH-1,2, U-triazole.

A solution containing 31.27 g of anisidine in 100 ml of dichlorobenzene and a solution containing H, 1 ml of phosphorus trichloride in 50 ml of dichlorobenzene are mixed. The reaction mixture is brought to 1000 DEG C. for 5 minutes and maintained at this temperature for 15 minutes. Then 10 g of 2- (1-oxobutyl) -hydrazide of β-methoxybenzoic acid are added and boiled for 15 minutes. Boil for 3 hours, cool to 600 ° C and pour on ice. It is filtered, the filtrate is decanted, the organic phase is extracted with hydrochloric acid and with water. Treat with activated carbon, filter, then add sodium hydroxide to pH 5. 454 173 17 Filter the resulting precipitate, dissolve it in 190 ml of methylene chloride, dry it, filter and drive off the solvent. Thus, 8.99 g of the desired crude product are recovered, which is recrystallized from ethyl acetate. After drying, 7.5 g of the desired product with a melting point of 125 DEG-126 DEG C. are obtained.

Erem§ fl ë1l fl i fl s = _21 (l-exabatlll-.favdfaßidjlx l-æeíwzsië fl aßee; acid, using_e_börian av_ešempel_ll. - Mix 12.95 g U-methoxybenzoic acid hydrazide and then add 15 ml toluene water. containing 8.56 ml of butyryl chloride in 25 ml of toluene The reaction mixture is kept under stirring for 16 hours at room temperature.

Add 50 ml of water, stir for 2 hours, centrifuge, wash with water and dry the crystals obtained. 15.85 g of the desired product with a melting point of 1300 DEG C. are thus obtained.

Example 12: 3-Ethyl-N- (3, M-dimethoxyphenyl) -5- (H-methoxyphenyl) -HH-1,2,3-triazole.

By working in the same way spa in the preparation of 3,1-bis- (N-methoxyphenyl) -5-propyl-HH-1,2, U-triazole (see Example 11) starting from 41 g of veratrilamine, U, N ml of phosphorus trichloride and 10 g of 2- (1-oxepropyl) -hydrazide of H-methoxybenzoic acid obtain 19.1 g of the crude product, which is recrystallized from ethyl acetate, then in toluene to obtain the desired product, melting at 1500 DEG C. .

Example 13: 5, U-bis- (U-methoxyphenyl) -5-butyl-HH-1,2,3-triazole.

By working as in Example 11 starting from 29.52 g of p-anisidine, 3.85 ml of phosphorus trichloride and 10 g of 2- (1-oxopentyl) hydrazide of U-methoxybenzoic acid, 7.77 g of crude product, which is recrystallized from ethyl acetate to give H, 7.7 g of the desired product, melting at 9 ° C.

(1-Exepenëvlthi fi aaaià avjtmsfexi- Eßnssesyzal anxän fi_ i_bëri fis affrempsklâ-) With stirring, 9.8 ml of valeryl chloride are charged into a solution containing the 1,2, U5 g of the H-methoxybenzicanoic acid mixture. hours, add 2 g of ice and stir for 15 minutes to destroy the excess hydrochloric acid, add water, stir for 30 minutes in an ice bath, filter, stir the crystals into a dough and dry, extracting 17.5 g of it. desired product, melting at 1120 ° C.

Example 1a: N, N-dimethyl-U- [2-ethyl-5- (H-methoxyphenyl) -HH-1,2,3-triazol-U-yli-benzenamine 9.7 g are stirred in the presence of hydrogen 3-ethyl-5- (U-methoxyphenyl) -H- (N-nitrophenyl) -H-1,2, U-triazole, H00 ml methanol and 50 ml 37% formaldehyde and 1.5 U Platinum oxide.

Platinum oxide is added over a quarter of an hour, then 9.7 g of 9.8% palladium on carbon 1 hour later. Filter, wash with methanol and drive off the solvent under reduced pressure. 12.3 g of product are obtained, which is chromatographed on silica (eluent: methylene chloride-methanol 9-1). 8.8 g of oil are recovered, to which is added U ml of ethyl acetate. You let it rest for 16 hours. The obtained crystals are centrifuged, washed and dried. 3.9 g of product are obtained, which melts at 1360 DEG C.

Example 15: N- [3-ethyl-5- (4-methoxyphenyl) -UH-1,2,8-triazol-H-yl] -benzenamine. A solution containing 23 g of tin chloride and 20 ml of concentrated hydrochloric acid is added at one time to a solution containing 10 g of 3-ethyl-5- (H-methoxyphenyl) -U- (N-nitrophenyl)- -1.2, U-triazole and 50 ml of concentrated hydrochloric acid. Stir vigorously for 2 hours. Filter and wash with 1N hydrochloric acid. The resulting precipitate is poured into 5N aqueous sodium hydroxide solution. You stir for 2 hours. White crystals are obtained, which are filtered, washed and dried at 110 DEG C. under reduced pressure. 12.5 g of crystals are thus obtained, which are dissolved in boiling toluene. Insoluble material is filtered and the filtrate is ice-cooled for 16 hours. Centrifuge, dry and obtain 5.8 g of crystals, melting at 216 ° C.

Example 16: Ethyl [5- (N-methoxyphenyl) -U-phenyl-HH-1,2, H-triazole-3] -acetate.

10 g of U-methoxy-N-phenyl-benzene-carbohydrazonamide (Synthesis, 360-1979) and 6.2 ml of triethylamine are dissolved in 50 ml of tetranydrofuran. It is cooled to 0 ° C, + 5 ° C and a solution of 5.76 ml of ethyl chloroformyl acetate in 20 ml of tetrahydrofuran is added dropwise. Filter to remove the triethylamine chlorohydrate. The tetrahydrofuran is evaporated at 100 DEG C. under reduced pressure. The residue is taken up in 50 ml of toluene, boiled for a few minutes and left to stand for 16 hours at 0 DEG C., +50 DEG C. Filter and obtain 9.2 g of the desired product, which melts at 130 DEG-1310 DEG.

Example 17: 5- (U-Methoxyphenyl) -U-phenyl-UH-1,2,8-triazole-acetic acid.

The mixture is stirred under argon at 60 DEG C. for half an hour. ethanol. The alcohol is driven off at 100 ° C under reduced pressure and 9.9 ml of 2N hydrochloric acid are added to the aqueous solution. It is kept for 16 hours at 454,173 0, +50 C. It is filtered, stirred several times into a dough with ice water to eliminate chlorides and dried at room temperature under vacuum 0.5 to 1 mm Hg. 3.6 g of product are obtained.

An_a1_¿s_¿ cl? al? M 3 O, PM = 309.31 calculated c z 62.37 H z 5.2L | N 7; 12,814 Found 62.7 5.2 13.1 Example 18: Ethyl [1,3-bis- (H-methoxyphenyl) -NH-1,2,3-triazole-3] -acetate A) A solution containing 20 g of 4 is refluxed. methoxy-N- (U-methoxyphenyl) -benzene-carbothioamide (Beilstein B-HBH) in 120 ml of ethanol. 20 ml of hydrazine hydrate are added. A homogeneous solution is obtained, and hydrogen sulphide develops rapidly. Once the development has stopped, you stop heating, add water, filter and drive off the ethanol. The resulting insoluble gum is extracted with methylene chloride, the extracts are washed with water, dried and the solvents are driven off under reduced pressure while heating at at least 50 ~ 35 ° C.

B) Place the product obtained in A in 350 ml of tetrahydrofuran, add 13.7 ml of tirethylamine. 9.9 ml of ethyl chloroformyl acetate in 20 ml of dry tetrahydrofuran are added. Stir for one and a half hours at 210 DEG C., filter, wash insoluble material in tetrahydrofuran and bring to dryness under reduced pressure while heating at fl'35 ° C. Dissolve the remaining gum in 200 ml of the toluene, reflux for 20 minutes. and drives off the solvent under reduced pressure. 25.63g of product are recovered. Tear this product in ether, cool for 1 hour, centrifuge, wash the crystals with very little ether and dry them.

20.285 g of product are obtained with a melting point of 14 DEG-14 DEG C. ~ 1115 DEG C. 454 173 21 C) The product obtained in B is dissolved in 250 ml of ethyl acetate, treated with activated carbon under reflux, concentrated to 50 ml. at atmospheric pressure. The resulting crystals are cooled, centrifuged and washed with ethyl acetate. The mixture is dried at 100 DEG C. under reduced pressure and 16.28 g of the desired product are extracted with a melting point of 156 DEG C.

Example 19: 3- (1-methylethyl) -1,5-bis- (β-methoxyphenyl) -UH- 1,2,2-triazole.

A solution containing H, U ml of phosphorus trichloride and 50 ml of anhydrous o-dichlorobenzene is charged for 20 minutes in a solution containing 31.6 g of p-anisialin 100 nl of o-aichlorobenzene. The reaction mixture is driven off at 110 DEG C. for 30 minutes. It is allowed to return to 50 DEG C. and 10 g of 2- (1-oxo-2-methylpropyl) -hydrazine of (N-methoxy) benzoic acid are added. Reflux for 3 hours. Cool the reaction solution to 600 DEG C. and pour on a mixture of ice and 2N hydrochloric acid. Stir for half an hour and filter. The filtrate is re-extracted with ether and filtered. The resulting clear solution is brought to pH 5 by the addition of concentrated sodium hydroxide. Stir for 30 minutes, centrifuge the resulting precipitate, wash with water and dry. 13.8 g of product are obtained, which is recrystallized from ethyl acetate. Thus 8 g of the desired product are obtained. Melting point 162 ° C.

Preparation of 2- (1-oxo-2-methylpropyl) -hydrazide of U-methoxy-benzoic acid.

A solution containing 11U, 2 ml of isobutynyl chloride and 20 ml of tetrahydrofuran is charged to a solution containing g of N-methoxy-benzoic acid hydrazide, 200 ml of tetrahydrofuran and 33.5 ml of triethylamine. Stir the resulting solution for 3 hours at room temperature, add 100 ml of water and extract with methylene chloride. The solvents are driven off under reduced pressure. After recrystallization from ethanol, 15.7 g of the desired product with a melting point of 1620 DEG C. are obtained.

Example 20: 3-Ethyl-U- (U-chlorophenyl) -5- (α-methoxyphenyl) -NH-1,2,2-triazole.

By working as before starting from p-anisidine and 2- (1-oxopropyl) -hydrazide of H-chlorobenzoic acid, the desired product is obtained, which melts at 1620 DEG C.

Preparation of 2- (2-oxopropyl) -hydrazide of U-chlorobenzoic acid.

While maintaining the temperature below 50 DEG C., 4.78 ml of propionyl chloride are charged into a solution containing 8.525 g of α-chlorobenzoic acid hydrazide and 25 ml of anhydrous pyridine.

The reaction solution is stirred for 15 hours at room temperature. Add ice, stir for 15 minutes to destroy the excess hydrochloric acid and then add 125 ml of distilled water a little at a time. A precipitate is formed. Stir for 30 minutes at 0 DEG + 50 DEG C., filter, wash the precipitate with water and dry under reduced pressure at 90 DEG C. 9.21 g of product are recovered, melting at 20 DEG C. The product obtained is recrystallized from ethanol. and recovers 6.77 g of 2- (1-oxopropyl) -hydrazide of N-chlorobenzoic acid, melting at 2060 DEG C.

Example 21: 3- (3,0-Methylenedioxy-phenyl) -5-ethyl-U- (U-methoxy-phenyl) -αH-1,2,1-triazole.

The procedure is as before starting from anisidine and 2- (1-oxopropyl) -hydrazide of 3,1H-methylene-dioxi-benzoic acid, and the desired product is obtained, which is recrystallized from absolute alcohol. melting point = 197 ° C. 55 454 173 Preparation of 2- (1-oxopropyl) -hydrazide of 3,0-methylenedioxy-benzoic acid.

Stir for 30 minutes at about 70 ° C a solution containing 23 g of 3, methylenedioxy-benzoic acid hydrazide (J. Org.

Chem. 20, 1955 ~ 855), 60 ml of propionic anhydride and 50 ml of pyridine. The resulting solution is kept on ice, centrifuged, the precipitate is washed with water and dried at 900 DEG C. under reduced pressure. 30.7 g of product are obtained, melting at 1380 DEG C., which is recrystallized from ethyl acetate to give 2U, 1 g of the desired product, which melts at 185 DEG C.

Example 22: 3,1-Diphenyl-5-methyl-3H-1,2,2H-triazole.

By working as above starting from 10 g of 2- (1-oxoethyl) -hydrazide and benzoic acid, 31.35 g of aniline and 8.5 g of phosphorus trichloride, 9.47 g of the desired product are obtained, which melts at 1630 ° C.

Example 23: N, N-Dimethyl-H- (H-phenyl-UH-1,2,1-triazol-3-yl) -benzenamine.

By working as indicated above, starting from U g of - (dimethylamino) -N-phenylbenzene-carbohydrazonamide (Ber 96. 2996 (1963)) and 130 ml of ethyl formate, 755 mg of the desired product are obtained, melting at 226 ° C.

Example ZÄ: N, N-dimethyl-H- [5-ethyl-U- (U-nitrophenyl) -UH-triazol-3-yl] -benzenamine acetyl-1-slim® 2-yl fi1fl.i2 °; N; < -.äeaßsfukafl fl ß; ÉíÉmÅ @; 55.6 g of U-dimethylaminobenzoic acid chloride, obtained by the action of thionyl chloride on dimethylaminobenzoic acid in carbon tetrachloride, are refluxed for 2 hours, 3 g of para-nitroaniline and 210 ml of pyridine. The reaction mixture is cooled to 0 DEG C. and 100 g of phosphorus pentasulfide are charged. Reflux for 2 hours, return to 400 DEG C. and pour on a mixture of hydrochloric acid and ice. Stir at room temperature for 1 hour, centrifuge, wash with water and dry the crystals formed. 187.3 g of product are obtained, which is poured into a 1N sodium hydroxide solution. Stir for 1 hour and filter. The crystals obtained are washed with water and dried. BÄ g product is thus obtained, which melts at 2100 C. âtssßi _'i ~ §im @ §ylami_f1 °; NL-l “: Hi fi aoieayl>: benäea-.lsaabe- hvâfazz fl amidl i A suspension containing 30 g of the product prepared in step A and 180 ml of ethanol is refluxed. 30 ml of hydrazine hydrate are added. The reflux is maintained for 15 minutes and 180 ml of distilled water are added. It is cooled to 100 C. It is centrifuged, washed with water and dried to form the crystals. 19 g of product are thus obtained, which melts at 17 DEG C. The ragga ai-siiezyi-B.-Lxeavi-ë-lftnraaosenyib fl ë-: riaaoi- ä-zíL-àeaße-amine is obtained. 5.8 ml of propionyl chloride are poured into a solution containing 19 g. g of the product prepared in step B, 200 ml of anhydrous tetrahydrofuran and 17.6 ml of triethylamine. The precipitate obtained is filtered off, washed with tetrahydrofuran and the solvent is removed from the filtrate under reduced pressure. The resulting residue is dissolved in toluene. The reaction mixture is refluxed for half an hour. The water and the solvent are eliminated. The resulting oil is dissolved under heat in ethyl acetate. 3.25 g of product are obtained by cooling, melting at 183 DEG-454 DEG-18 DEG C. The mother liquors are chromatographed on silica; elutes with a mixture of methylene chloride-methanol (95-5) to recover 7.7 g of product.

Example 25: N 'H' - [β-ethyl-HH-1,2,2, N-triazol-U, 5-diyl] -N, N, N ', N'-tetramethyl-bis-benzenamine.

A mixture containing 7.3 N, N-dimethyl-U- [E-ethyl-U- (U-nitrophenyl) -UH-1,2, U-triazol-3-yl] -benzene amine, 300 ml of methanol is hydrogenated. , H0 ml formaldehyde, 1, N g platinum oxide. Filter once the reaction is complete, wash with methylene chloride, evaporate the solvents under reduced pressure. 8 g of an oil are obtained, which is purified by chromatography on silica eluting with a mixture of methylene chloride-methanol (95 ~ 5). 6.7 g of an oil are obtained, which crystallizes slowly in ethyl acetate. melting point 178 ° c then 186 ° c.

Example 26: M, 41- (3-ethyl-HH-1,2,4-cryazol-M, 5-alkyl) -bis-phenol.

Reflux for 1 hour a solution containing 6 g of 3, U-bis (--methoxyphenyl) -5-ethyl-UH-1,2, U-triazole and 25 ml of a hydrobromic acid solution at H80 C. The hydrobromic acid is distilled under vacuum , dissolve the crystalline residue in 50 ml of water while heating and add ammonia to alkaline pH. The desired product is obtained, which is recrystallized from dimethylformamide. Cool for 1 hour, spin; wash with a mixture of dimethylformamide and water (3 - U) and dry the crystals obtained. Thus, 395 g of the desired product with a melting point of 317 DEG-3180 DEG C. are obtained.

Example 27: U- (3-ethyl-α-phenyl-UH-1,2,2-Hptriazol-5-yl) -phenol.

A solution containing 3.86 g of 3-ethyl-5- (U-methoxyphenyl) -U-phenyl-HH-1,2, U-triazole and ml of an H8% hydrobromic acid solution is refluxed for 1 hour. The hydrobromic acid is driven off under reduced pressure, the crystals obtained are stirred with 20 ml of water, ammonia is added until an alkaline pH value is obtained. It is left to stir overnight. It is centrifuged, washed with water and dried at 900 DEG C. under reduced pressure. 3.65 g of product are recovered, which is recrystallized from methanol.

It is cooled, centrifuged, the crystals are washed by stirring to a dough in methanol and dried at 900 DEG C. under reduced pressure. 3.2ü5 g of the desired product are obtained, which melts at 275 ° C.

Example 28: N, N-Dimethyl-U- [5-ethyl-H- (4-methoxyphenyl) -HH-1,2,3-triazol-3-yl] -benzenamine.

A suspension containing 8.5 g of β-dimethylamino-U'-methoxy-benzenecarbothiamide and 50 ml of ethanol is refluxed.

9 ml of hydrazine hydrate are charged. Reflux for about half an hour, add ice-cold water and extract with methylene chloride. The solvent is driven off under reduced pressure to give 10 g of residue, which is taken up in 10 ml of tetrahydrofuran. 17 ml of triethylamine are added and 11.5 ml of propionyl chloride are charged over 10 minutes. The reaction mixture is stirred for half an hour, the precipitate is centrifuged and washed with tetrahydrofuran. The solvent is driven off the filtrate under reduced pressure. An oil is obtained, which is dissolved in 200 ml of toluene and refluxed for 2 hours. The solvent is evaporated off under reduced pressure and the residue is taken up in a mixture of 100 ml of hydrochloric acid and 200 ml of water.

The attenuate phase is extracted with ether and filtered. The filtrate is brought to pH 6 by the addition of concentrated sodium hydroxide, then extracted with methylene chloride. 7.1 g of a rubber are thus obtained, which is chromatographed on silica eluting with the methylene chloride-methanol mixture (95-5). Thus 2, 2 g of the desired product are obtained, which are recrystallized from a mixture of toluene-ether (1-1). melting point 1h8 ° c.

Preparation of U-dimethylamino-N- (H'-methoxyphenyl) -benzene-carbothiamide.

13.6 g of p-anisidine are charged to a solution containing 22.2 g of U-dimethylaminobenzoic acid chloride in 8H ml of anhydrous pyridine. The resulting solution is refluxed for * 1 hour. cool to 30 ° C, add 53 g of phosphorus pentasulfide and reflux for 2 hours. The reaction mixture is poured onto a mixture of concentrated hydrochloric acid and ice water. Stir for 1 hour, centrifuge, wash the precipitate with 0.1 N hydrochloric acid and stir the resulting precipitate for 1 hour with 300 ml of 1N sodium hydroxide.

Centrifuge, wash with water and dry the crystals obtained. 13.5 g of the desired product are obtained, which melts at 1920 DEG C.

Example 29: 3-Ethyl-5- (3,1-dimethoxyphenyl) -4- (β-methoxyphenyl) -αH-1,2,2-triazole.

By working as before starting from 29.29 g of p-anisidine ,. 382 ml of phosphorus trichloride and 10 g of 2- (1-oxopropyl) hydrazide of 3,1-dimethoxybenzoic acid give 11 g of the desired product in crude form, which is recrystallized from ethyl acetate. Melting point = 1H8 ° C.

Preparation of 2- (1-oxopropyl) -hydrazide of 3,0-dimethoxybenzoic acid.

16.2 g of 3,1'-dimethoxybenzoic acid hydrazide (Am. Soc, Igg. 1901) and H0 ml of propionic anhydride are heated at about 650 DEG C. for 30 minutes. The excess anhydride is driven off under reduced pressure and the reaction solution is poured into a solution containing 200 ml of methylene chloride and 50 ml of ethyl acetate. 550 ml of the solvent are distilled off under normal pressure. The resulting crystals are ice-cooled, centrifuged and washed with ethyl acetate and dried. 20.2 g of product with a melting point of 1420 DEG C. are obtained.

Example 30: Pharmaceutical compositions Tablets having the following composition have been prepared: product according to Example 1 excipient q.s. for 1 tablet up to 50 ms 350 ms (Examples of excipients: lactose, talc, starch, magnesium stearate).

Example 31: Pharmaceutical compositions.

Tablets having the following composition have been prepared: product according to Example 25 50 mg of excipient q.s. for 1 tablet up to 350 mg (Examples of excipients: lactose, talc, starch, magnesium stearate).

H fl ëezsëkaiea fl x 962 a fl eleeliekê. ekåixiåeïea 110: ars fi akåee i 21211126; The test used is inspired by the technique of Singmund et al. (Proc. Soc. Exp. Biol. And Med., 1957, Ga., 729) using phenylbenzoic acid with intraperitoneal administration to induce in mice repeated extending and twisting movements, which are prevented or eliminated by analgesics.

This syndrome can be considered as a manifestation of a diffuse abdominal pain. A 0.02% aqueous solution of BO 454 173 29 phenylbenzoquinone containing U% ethanol, injected in a volume of 0.25 ml per mouse, is used.

The tested products are administered orally half an hour before the injection of phenylbenzoquinone, the mice being fasted for 6 hours.

The extensions are observed and counted for each mouse during an observation period of 15 minutes starting 5 minutes after the phenylbenzoquinone injection.

The results are expressed by AD50, i.e. the dose, which allows a 50% reduction in the number of extensions in relation to the control animals. The AD 50 value obtained was 7 mg / kg.

E fl dezsëkniaaax 282 anelseíziska skïixiieiea ms Bredak; .tears .i sXsmQ-lsnßâ eßb. 38; This test is based on the observation of Koster et al.

(Fed. Proc. 1959, lay, 412) according to which the intraperitoneal injection of acetic acid in mice causes repeated extension and twisting movements, which can be considered as manifestations of a diffuse abdominal pain, as they are alleviated by analgesics. The acetic acid is injected at a dose of 100 mg / kg or 1 ml of a 1% aqueous solution per 100 g body weight to female mice weighing 20 - 22 g, which have been fasted for 7 hours. The product is administered per os 30 minutes before the injection of the acetic acid into groups of 10 animals, each experiment comprising a control group, which receives the vehicle. minutes after the injection of the irritant, the extensions and twists of each animal for a period of 15 minutes are counted. 454 173 The analgesic effect at each dose of the product examined is expressed as a percentage of protection in relation to the average number of movements observed in the controls, which received only the acetic acid. ADBO, or the dose required to reduce the number of extensions by 50%, is calculated using the least squares method.

The AD50 value obtained for the products of Examples 25 and 28 was close to mg mg / kg. _

Claims (15)

454 173: SI Patent Claim Compounds of formula (I) N - NI k NRR 1 (I) R 2 - Ra Ru wherein R 1, R 2, R 3 and R 4, the same or different, at any position in the benzene nucleus, represent a hydrogen atom, a hydroxyl group, an alkyl group having 1-4 carbon atoms, an Oalk1, wherein alk1 represents an alkyl group having 1-4 carbon atoms, a group NH2, Nnalkz, wherein alkz represents an alkyl group having 1-4 carbon atoms, / alk'3 a group N -alk3 wherein alk3 and alk'3 are the same or different, represents an alkyl group having 1-4 carbon atoms, a halogen atom, a group CF3 or NO2, or R1 and R2 and / or R3 and R4 together form a methylenedioxy group, R represents a hydrogen atom, a group a1k4, wherein alk4 represents an alkyl group having 1-4 carbon atoms, a group -CH2CO2H or -CH2CO2alk5, wherein alks represents an alkyl group having 1-4 carbon atoms, and addition salts thereof with acids for use as a therapeutic. Compounds for use as a therapeutic according to claim 1, characterized in that they have the formula (ï ') R' (IW 454 173 32 wherein R 1, R 2, R 3 and R 4 have the meanings given in claim 1, R 'represents a group alk4, a1k4 denotes an alkyl group having 1-4 carbon atoms, a group -CH2CO2H or -CH2CO2alk5, wherein alks denotes an alkyl group having 1-4 carbon atoms, and addition salts thereof with acids, for use as a therapeutic. Compounds according to claim 2, characterized in that they have the formula (I ") zk * NR '(I") R' R ''4 wherein R'1, R'2, R'3 and R'4, equal or different, in any position in the benzene nucleus, has the same meanings as in claim 2 for R'1, R'2, R'3 and R'4, wherein R'1, R'2, R'3 and R 4, however, cannot simultaneously denote a hydrogen atom, R 'has the same meaning as R' in claim 2, and addition salts thereof with acids. Compounds of the formula I according to Claim 1 for use as a therapeutic agent, characterized in that they consist of the compounds - 3,4-bis (4-methoxyphenyl) -5-ethyl-4H-1,2,4 -triazole-4,4 '- (3-ethyl-4H-4,2,4-triazole-4,5-diyl) -N, N,'fN', N'-tetramethyl -bis (benzenamine) -N , N-dimethyl-4- [E-ethyl-4- (4-methoxyphenyl) -4H-1,2,4-triazol-3-yl] -benzenamine and addition salts thereof with acids. 5. Pharmaceutical compositions, characterized in that they contain as active substance at least one compound of formula (I) 454 175 NN in IR WHEN 1 (I) , the same or different, in any position in the benzene nucleus, denotes a hydrogen atom, a hydroxyl group, an alkyl group having 1-4 carbon atoms, an Oalk1, wherein alk1 denotes an alkyl group having 1-4 carbon atoms, a group NH2, N denotes an alkyl group having 1-4 carbon atoms, a group / alk'3 N-alk3 wherein alk3 and a1k'3 heal or different, denotes an alkyl group having 1-4 carbon atoms, a halogen atom, a group CF3 or NO2, or R 1 and R 2 and / or R 3 and R 4 together form a methylenedioxy group, R represents a hydrogen atom, a group alk4, wherein alk4 represents an alkyl group having 1-4 carbon atoms, a group -CH2CO2H or -CH2CO2alk5, wherein alk5 represents an alkyl group having 1-4 carbon atoms, and addition salts thereof with acids. Compounds, characterized in that they have the formula (IIII) NN II k I 'R' NR ... 1 (I) Ra H3 Ra wherein R1, R2, R3 and R4 are the same or different, in which position as preferably in the benzene nucleus, represents a hydrogen atom, a hydroxyl group, an alkyl group having 1-4 carbon atoms, an Oalk1, wherein alk1 represents an alkyl group having 1-4 carbon atoms, a group NH2, NHa1k2, wherein alkz represents an alkyl group having 1-4 carbon atoms, a group 454 173 34 / alk'3 N-alk3 wherein alk3 and alk'3, equal or different, represent an alkyl group having 1-4 carbon atoms, a halogen atom, a group CF3 or NO2, or form R1 and R2 and / or R 3 and R 4 together form a methylenedioxy group, R "represents an ethyl, n-propyl, n-butyl group, a group -CH 2 CO 2 H, or -CH 2 CO 2 alk 5, wherein alk 5 represents an alkyl group having 1-4 carbon atoms, and addition salts hence with acids. Compounds of formula (I "') according to claim 6, characterized in that R" represents an n-ethyl- or n-butyl group, a group -CH 2 CO 2 H or -CH 2 CO 2 alk 5, wherein alks have 1-4 carbon atoms , and addition salts thereof with acids. Compounds of formula (I "') according to claim 6, characterized in that R" represents an ethyl group and addition salts thereof with acids. ' Compounds of the formula (I "'), as defined in any one of claims 6 to 8, characterized in that R1 represents a hydrogen atom, and addition salts thereof with acids. Compounds of formula (I "'), as defined in any one of claims 6 to 9, characterized in that R 2 represents a group Oalk 1, defined in claim 4, in any position in the benzene nucleus, and addition salts hence with acids. Compounds of formula (I "'), defined in claim 10, characterized in that R 2 represents a methoxy group in the 4-position, and addition salts thereof with acids. Compounds of formula (I "'), as defined in any one of claims 6 to 11, characterized in that R 3 represents a hydrogen atom and R 4 represents a methoxy group, a chlorine atom, a group CF 3, a methyl group or a group NO 2 , in any position in the benzene nucleus, and addition salts thereof with acids. Compounds of formula (I "'), as defined in any one of claims 6 to 11, characterized in that R 3 represents a methoxy group in the 4-position and R 4 in any position represents a methoxy group, a chlorine atom, a group CF3, a methyl group or a group NO2, and addition salts thereof with acids 454 173 55 Compounds according to any one of claims 6 to 13, characterized in that they have the following names: - 3,4-bis (4-methoxyphenyl) -5-ethyl-4H-1,2,4-triazole - 4,4 '- (3-ethyl-4H-1,2,4-triazole-4,5-diyl) -N, N, N', N'-tetramethyl -bis (benzenamine) - N, N-dimethyl -4-N-ethyl-4- (4-methoxyphenyl) -4H-1,2,4-triazol-3-yl] -benzenamine and addition salts thereof with acids. 15. A process for the preparation of the compounds of the formula (I "')" N "*" N 1 (Ivan): Ru wherein R 1, R 2, R 3 and R 4, the same or different, in any position in the benzene nucleus, represent a hydrogen atom, a hydroxyl group, an alkyl group having 1-4 carbon atoms, an Oalk1 wherein alk1 represents an alkyl group having 1-4 carbon atoms, a group NH2, NHalk2, wherein alk represents an alkyl group having 1-4 carbon atoms, a group alk'3 N- alk3 wherein alk3 and a1k'3, equal or different, represent an alkyl group having 1-4 carbon atoms, a halogen atom, a group CF3 or NO2, or R1 and R2 and / or R3 and R4 together form a methylenedioxy group, R "represents an ethyl, n-propyl, n-butyl group, a group -CH 2 CO 2 H, or -CH 2 CO 2 alk 5, wherein alks represents an alkyl group having 1-4 carbon atoms, and addition salts thereof with acids, defined in any one of claims 1 - 10, and salts thereof, characterized in that 'a) reacting a compound of formula (II) 454 173 36 HN - NH il? wherein R1, R2 and R3 have the meanings given above, for the action of a compound of formula (III) /, NH2 - (III) Ru wherein R3 and R4 are defined as above, in the presence of a dehydrating agent, for the preparation of the corresponding compound of the formula (I "') N' - 'N (I || v) which is, if desired, subjected to the action of an acid to produce salts therefrom or b) exposes a compound of formula (IV) S 11. Wherein R 1, R 2, R 3 and R 4 have the meanings given above, for the action of hydrazine to give a compound of formula (V) N - »m 2 C 1 NH 4 in (V) which is exposed - either to the action of an acid or a functionally acid-derived XCO 2 H, wherein X represents a hydrogen atom or an alkyl group having 1-4 carbon atoms, to produce the compound of formula (VI) O Il c R. By the heating for the preparation of the compound a formula (IA) 'Ní-N 1, / I NJL \\ R (I) U corresponding to a compound of the formula I "', wherein R 1, R 2, R 3 and R 4 are defined as cyano and X represents a hydrogen atom or an ethyl, n-propyl or n-butyl group, which compound of formula (IA) is, if desired, subjected to the action of an acid to prepare the salt therefrom, or for the action of a compound of formula (VII) O Hal-C-CH 2 -CO 2 -alk5 (VII) wherein Hal represents a halogen atom and alks is defined as above for the preparation of of the compound of formula (IB) N 'NN 11 CH 2 CO 2 alk (I) .Ru corresponding to a compound of formula I "', wherein R 1, R 2, R 3 and R 4 are as defined above, and R" denotes a group -CH 2 CO 2 -alks, wherein alk 5 is defined as above, which compound of formula (IB) is, if desired, subjected to the action of an acid, to produce therefrom the salt, or which compound may, if desired, exposes to i action of an acid hydrolyzing agent for the preparation of compounds of formula (IC) N_N I k N c fl z cozn R1 (IC) Ra H3 U corresponding to a compound of formula I "', wherein R1, R2, R3 and R4 are defined as above , and R "represents a group -CH 2 CO 2 H, which compound of the formula (ICL if desired) is subjected to the action of an acid to produce the salt therefrom.